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British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660

Review
Osteoradionecrosis of the jaws: current understanding
of its pathophysiology and treatment
Andrew Lyons a,∗ , Naseem Ghazali b
aDepartment of Oral & Maxillofacial Surgery, 23rd Floor Guy’s Tower, London SE1 9RT, United Kingdom
bMaxillofacial Unit, Guy’s, King’s & St Thomas Schools of Medicine and Dentistry,
King’s College Hospital, Denmark Hill, United Kingdom

Accepted 12 April 2008

Available online 17 June 2008

Abstract

During the past 80 years a number of theories about the pathogenesis of osteoradionecrosis (ORN) have been proposed, with consequent
implications for its treatment. Until recently tissue hypoxia and its consequences were accepted as the primary cause, and this led to the use of
hyperbaric oxygen (HBO) for both treatment and prevention of complications of radiotherapy in the head and neck. The benefit of HBO has
not been validated. A new theory for the pathogenesis of ORN has proposed that damage to bone is caused by radiation-induced fibrosis. Cells
in bone are damaged as a result of acute inflammation, free radicals, and the chronic activation of fibroblasts by a series of growth factors.
New treatments have therefore been devised that include pentoxifylline, a vasodilator that also inhibits fibrosis, and tocopherol (vitamin E) to
reduce damage caused by free radicals. Impressive results in terms of reversing the process of ONR have been reported using these agents. It
has been suggested that this theory and these agents could be the basis of future treatment and prevention of ORN.
© 2008 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Keywords: Osteoradionecrosis; Radiation; Mandible; Pathophysiology; Radiation-induced fibrosis; Pentoxiphylline

Introduction ORN is recognised, it is irreversible and extremely difficult

to treat. We explore recommendations and current theories
In 1922, Regaud published what was arguably the first about its aetiology, pathogenesis, and treatment.
report about osteoradionecrosis (ORN) of the jaws after
radiotherapy.1 During the past 80 years, this condition has
persisted as a consequence of radiotherapy for head and Background
neck cancer in an appreciable minority of patients. Since
then several theories have been propounded to explain its Terminology and definition
cause including the release of histamine, the theory of radi-
ation, trauma, and infection2 and, until recently, the most Various terms and definitions of ORN are given in
widely accepted theory of hypoxia, hypovascularity, and Tables 1 and 2. Perhaps the most widely used definition
hypocellularity.3 There is a general consensus, however, of ORN that affects the jaws is based on clinical presen-
about the clinical presentations of ORN, which are pain, tation and observation: irradiated bone becomes devitalised
drainage, and fistulation of the mucosa or skin that is related and exposed through the overlying skin or mucosa without
to exposed bone in an area that has been irradiated. Once healing for 3 months, without recurrence of tumour.4
Although widely used, this definition is far from perfect,
∗ Corresponding author. and can be criticised for two reasons; the duration of the

0266-4356/$ – see front matter © 2008 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bjoms.2008.04.006
654 A. Lyons, N. Ghazali / British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660

Table 1 inconsistencies in the length of follow-up between studies,

Terms used to describe osteoradionecrosis and limited data from prospective studies.
Radiation osteitis 4
ORN affects the mandible more often than the maxilla
Radio-osteonecrosis 5
2
or any other bones of the head and neck.12 Its incidence in
Radiation osteomyelitis
Osteomyelitis of irradiated bone 6 the mandible is between 2% and 22% of cases, and it most
Osteonecrosis 7 often affects the body.10 It is rare after radiation of less than
Radio-osteomyelitis 8 60 Gy, but more common when brachytherapy is used (the
Septic osteoradionecrosis 9
mandible must be in the area of treatment to be at risk).12
Post-radiotherapy osteonecrosis 10
However, the incidence of ORN is thought to be less common
after hyperfractionated radiotherapy at 72–80 Gy, or moder-
bone’s exposure to radiation, and the definition of “devi- ately accelerated fractionated radiotherapy together with a
talised” bone.5 Some studies have not commented on the boost of 64–72 Gy. Recent reports have suggested that when
length of exposure, while others have suggested a period chemotherapy is added to radiotherapy the incidence of ORN
of up to 6 months.4,6–9 With a short period of observa- may be increased13,14 whereas the use of intensity-modulated
tion, simple radionecrosis of the mucosa with no underlying radiotherapy may reduce it.15
necrotic bone can be mistaken for ORN. The observation Factors that are thought to affect the development of ORN
period should also take into account the time taken for include size and site of the tumour, dose of radiation and
complete healing after any operation or extraction, which type of mandibular resection, injury, or dental extractions:
can take up to four weeks. Conversely, a period of passive infection; immune deficiencies; and malnutrition. Many
observation of less than 6 months is difficult to justify in patients with oral cancer have other serious diseases and have
clinical practice because some earlier intervention is often often had a long history of alcohol and tobacco misuse.16
necessary.5 These, combined with poor nutrition and unsatisfactory oral
Regaud noted the absence of a clear line of demarcation hygiene, place such patients at high risk of developing
between devitalised and vital bone.1 Attempts to clarify this ORN.
ambiguity have led to calls for ORN to be defined by radio- Dental disease and dentoalveolar surgery, in particular
logical evidence of bony necrosis within the radiation field,10 dental extractions after radiotherapy, are well-established
or through histological examination of necrotic bone at the predisposing factors to ORN; the documented incidence of
time of eventual resection.11 ORN after extractions is about 5%. Its incidence is three times
higher in dentate than in edentulous patients, mainly as a
result of injury from extractions and infection from periodon-
Epidemiology and risk factors for the development of
tal disease.17–20 The risk of developing ORN after extractions
osteoradionecrosis
is higher in posterior mandibular teeth with roots that lie
below the mylohyoid line, and when an atraumatic extraction
Analysis of epidemiological studies of ORN does not provide
was not possible.21
accurate data about incidence and prevalence of ORN in the
jaws because of the lack of agreement about its definition,
Clinical range of osteoradionecrosis and its staging
Table 2
Definitions of osteoradionecrosis Early ORN may be asymptomatic even though the its
main features of exposed devitalised bone through ulcer-
First author Reference No Definition
6
ated mucosa or skin can be seen clearly. Pain is a common
Beumer “When bone in the radiation field was
symptom and some patients have presented with intractable
exposed for at least 2 months in the
absence of local neoplastic disease” pain. Other associated symptoms include dysaesthesia, hal-
Marx 8 “An area greater than 1 cm of itosis, dysgeusia, and food impaction in the area of exposed
exposed bone in a field of irradiation sequestra.22,23 In severe cases, patients can present with fis-
that had failed to show any evidence tulation from the oral mucosa or skin, complete devitalisation
of healing for at least 6 months”
9 of bone, and pathological fractures.
Hutchinson “An area of exposed bone (mandible)
present for longer than 2 months in a The interval between radiotherapy and the onset of ORN
previously irradiated field, in the can vary, but most occur between 4 months and 2 years.
absence of recurrent tumour” ORN usually develops during the first 6 to 12 months after
Epstein 7 “an ulceration of the mucous radiotherapy, however, the risk remains for life, albeit to a
membrane with exposure of necrotic
lesser degree.24 It may present much earlier after a local
bone”
Harris 4 “Irradiated bone becomes devitalised traumatic event. Epstein et al. reported that ORN usually
and exposed through the overlying presented about 4.5 months after radiotherapy in cases asso-
skin or mucosa, persisting without ciated with dental or surgical injury,23 but in most it may
healing for 3 months in the absence present after follow-up of the incidence studies. Berger and
of tumour recurrence”
Symington reported two late presentations, one 45 years after
 A. Lyons, N. Ghazali / British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660 655

a radium implant, and the other 38 years after external beam ing factor”.5 The pathophysiological sequence suggested
treatment.25 by Marx is: irradiation; formation of hypoxic-hypocellular-
Over the years, many staging systems have been pro- hypovascular tissue; and breakdown of tissue (cellular death
posed to aid treatment and provide classifications for and breakdown of collagen that exceeds cellular replica-
research.8,10,12,23,26 The classifications were based on vari- tion and synthesis) driven by persistent hypoxia that can
ous criteria, including the presence of: soft tissue dehiscence cause a chronic non-healing wound (a wound in which
necrotic bone, the amount of necrotic bone oro-cutaneous fis- metabolic demands exceed supply)5 (Fig. 1). These explana-
tulae and pathological fracture. The Wilford Hall hyperbaric tions formed the cornerstone for the use of hyperbaric oxygen
oxygen ORN protocol proposed by Marx stages ORN in its (HBO) in the treatment of ORN.
response to his HBO treatment protocols.8 The late effects The therapeutic value of HBO was originally observed
on normal tissue (LENT) and subjective, objective, manage- in controlled in vivo experiments on burns in which daily
ment and analytic (SOMA) scales proposed by the Radiation increases in the oxygen tensions in hypoxic tissues were
Therapy Oncology Group are scoring systems to stage the found to encourage capillary angiogenesis, proliferation of
late complications of radiation, and may also be used to stage fibroblasts, and synthesis of collagen.27 Furthermore,HBO
ORN.27 can also be bactericidal or bacteriostatic to many pathogens.31
Mainous et al. were probably the first to suggest the use of
HBO for the management of ORN.32 Since then it has been
Theories of the pathophysiology of advocated for preoperative and postoperative treatment in
osteoradionecrosis: a critical appraisal high-risk patients having teeth extracted or other operations.
HBO has been used with conservative measures to pre-
Watson and Scarborough reported three crucial factors in vent the onset of ORN.33,34 Marx et al. compared HBO with
the development of ORN based purely on clinical observa- penicillin alone in a randomised trial to prevent the onset of
tions; exposure to radiotherapy above a critical dose; local ORN after dental extraction. The HBO group had a lower
injury; and infection.28 Early experimental models of the incidence of ORN than the penicillin alone group.33 How-
pathophysiology of ORN showed evidence of bacteria in tis- ever, subsequent studies24,35,36 showed an incidence of ORN
sues affected by ORN, and documented microscopic tissue of less than 5% after careful radiotherapy after dental extrac-
changes, namely thickening of arterial and arteriolar walls, tion without HBO. These are valid arguments for the use of
loss of osteocytes and osteoblasts, and the filling of bony HBO to prevent ORN.
cavities with inflammatory cells.29 The results of HBO in treating established ORN are not
This gained popularity when Meyer proposed his radia- convincing. In Marx’s HBO protocol study, only 15% of
tion, trauma and infection theory.2 He suggested that injury (60) patients responded to HBO alone; most had operations
provided the opening for invasion of oral microbiologi- if they did not respond to HBO, 14% had sequestrectomy,
cal flora into the underlying irradiated bone. Other authors and 70% major reconstruction.8 These results suggested that
agreed and referred to ORN as secondary infection after HBO without aggressive surgical management was inade-
injury to devitalised bone, and even as radiation-induced quate, and this was noted in subsequent studies of HBO in
osteomyelitis.30 Meyer’s theory lasted for a decade and ORN.23,37–40
became the foundation for the popular use of antibiotics with For advanced presentations of ORN including patholog-
surgery to treat ORN. ical fracture, fistula, and complete devitalisation of bone,
After an in-depth study of Meyer’s hypothesis, Marx pro- segmental mandibular resection with free vascularised bone
posed the hypoxic-hypocellular-hypovascular theory as a grafting has become standard treatment as it is increasingly
new way of understanding the pathophysiology of ORN.3 clear that HBO alone is not beneficial.21 Maier et al. showed
He noted that there was no injury before the onset of ORN in that patients with advanced ORN who had debridement and
35% of his cases, and found that the microbiological profile were given antibiotics were just as likely to recover as those
of ORN was different from that of osteomyelitis. Micro- who were also given HBO.41 Taking this a step further, Gal
biological investigation of bone affected by ORN showed et al. showed that patients who had resection and reconstruc-
various microbes on its surface, which were possibly contam- tion with a free osteocutaneous flap but without the use of
inants. This contrasted sharply with cultures of long bones perioperative HBO had fewer complications that those who
with osteomyelitis and infected bone grafts, which consisted had HBO.42
primarily of one pathogen, usually a staphylococcal species. The widespread use of HBO for the treatment of mandibu-
He also found that composite irradiated tissues were more lar ORN may be considered largely theoretical or anecdotal
hypoxic than those that had not been irradiated. because of the paucity of controlled trials and the lack of
Marx concluded that: “ORN is not a primary infection any unified assessment of the improvement of symptoms.
of irradiated bone, but a complex metabolic and homeo- Recently, a random, placebo-controlled, double-blind study
static deficiency of tissue that is created by radiation-induced was conducted in France to assess the efficacy and safety
cellular injury; micro-organisms play only a contaminating of HBO for the treatment of overt mandibular ORN.43 All
role in ORN; and trauma may or may not be an initiat- patients had at least one clinical and one radiological sign of
656 A. Lyons, N. Ghazali / British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660

Fig. 1. Pathophysiology of osteoradionecrosis according to Marx.

ORN, but those with fracture or bony erosion of the inferior after treatment with HBO, which suggested that these tissues
border were excluded. Sixty-eight patients were randomly were hypoxic before they were treated. However, Rudolph et
allocated to the HBO and placebo groups, but the trial was al. found comparable TcPO2 in irradiated and non-irradiated
terminated prematurely because it failed to show any ben- skin,46 so the importance of actual tissue hypoxia in tissues
efits of HBO over placebo in recovery (19% against 33%, affected by ORN has not been proved, and is a real challenge
respectively); neither did it slow the progression of disease, to Marx’s theory.
or relieve pain. The authors concluded that better recovery
rates seen in patients given a placebo were likely to be a
result of improvements in conservative treatments. However, Contemporary understanding of the pathophysiology
in this trial HBO was the only treatment and not an adjunct of osteoradionecrosis: radiation-induced
to surgery as is more commonly utilized. fibroatrophic theory
In a Cochrane Collaboration review of the use of HBO
in late radiation injury of tissue,44 no other unpublished ran- Radiation-induced fibrosis is a new theory that accounts
dom trial into the treatment of ORN with HBO was found for the damage to normal tissues, including bone, after
apart from one further trial by Marx,45 which reported that radiotherapy.47 It was introduced in 2004 when recent
HBO improves bony healing and maintains bony volume after advances in cellular and molecular biology explained the
non-vascularised reconstruction of hemimandibular defects progression of microscopically observed ORN.
in irradiated areas. However, this is in a chapter in a text- The histopathological phases of the development of
book, and the authors of the Cochrane review comment that ORN closely reflect those seen in chronic healing of trau-
the description of the trial is sketchy. matic wounds.48 Three distinct phases are seen: the initial
The lack of significant results obtained with HBO in prefibrotic phase in which changes in endothelial cells pre-
tissues affected by ORN may be attributed to the flawed dominate,together with the acute inflammatory response; the
conclusion that the late presentation and irreversible nature constitutive organised phase in which abnormal fibroblas-
of ORN is related to tissue hypoxia, particularly in areas tic activity predominates, and there is disorganisation of the
of necrotic hypovascular tissues. Beehner and Marx found extracellular matrix; and the late fibroatrophic phase, when
higher levels of oxygen tension in tissues affected by ORN attempted tissue remodelling occurs with the formation of
based on transcutaneous partial oxygen pressure (TcPO2 ) fragile healed tissues that carry a serious inherent risk of late
 A. Lyons, N. Ghazali / British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660 657

reactivated inflammation in the event of localinjury. Inter- To reverse changes in reactive oxygen species that pro-
estingly, Marx had reached similar conclusions, but thought duce radiation-induced fibrosis and ultimately ORN, new
that the driving force of the sequence of events was persistent therapeutic regimens have been developed.52 Pentoxifylline
tissue hypoxia. is a methylxanthine derivative that exerts an anti-TNF␣
The theory of radiation-induced fibrosis suggests that effect, increases erythrocyte flexibility, dilates blood vessels,
the key event in the progression of ORN is the activa- inhibits inflammatory reactions in vivo, inhibits proliferation
tion and dysregulation of fibroblastic activity that leads to of human dermal fibroblasts and the production of extracel-
atrophic tissue within a previously irradiated area. After lular matrix, and increases collagenase activity in vitro. It
radiotherapy the endothelial cells are injured, both from direct is given with tocopherol (vitamin E), which scavenges the
damage by radiation and from indirect damage by radiation- reactive oxygen species that were generated during oxidative
generated reactive oxygen species or free radicals. Injured stress by protecting cell membranes against peroxidation of
endothelial cells produce chemotactic cytokines that trigger lipids, partial inhibition of TGF-␤1, and expression of pro-
an acute inflammatory response and then generate a further collagen genes, so reducing fibrosis. These two drugs act
release of reactive oxygen species from polymorphs and other synergistically as potent antifibrotic agents. In animal studies
phagocytes.49 The destruction of endothelial cells, coupled neither drug alone was capable of reversing reactive oxygen
with vascular thrombosis, lead to necrosis of microvessels, species.21
local ischaemia, and tissue loss. Loss of the natural endothe- In a recent phase II clinical trial, 18 consecutive patients
lial cell barrier allows seepage of various cytokines that cause who had had radiotherapy for head and neck cancer had
fibroblasts to become myofibroblasts. mandibular bone roughly 13.4 mm long exposed.53 Over 7
The reactive oxygen species-mediated release of cytokines years all had been given daily pentoxifylline 800 mg com-
such as tumour necrosis factor ␣ (TNF-␣), platelet-derived bined with vitamin E 1000 IU orally for 6–24 months. The
growth factor, fibroblast growth factor ␤, interleukins 1, eight most seriously affected patients were also given clo-
4, and 6, transforming growth factor ␤1 (TGF-␤1), and dronate 1600 mg/day 5 days a week. Clodronate is a new
connective tissue growth factor, result in unregulated fibrob- generation bisphosphonate that inhibits bone resorption by
lastic activation and the myofibroblast phenotype persists.49 reducing the number and activity of osteoclasts.54 When
These myofibroblasts are characterised by unusually high an ORN-like disease of mandibular bone has been reported
rates of proliferation, secretion of abnormal products of the in patients who had been given this treatment for cancer-
extracellular matrix, and a reduced ability to degrade such associated hypercalcaemia or metastatic osteolytic lesions,55
components. Deregulation of the proliferation of fibroblasts but unlike previous bisphosphonates clodronate has been
and metabolism are similar to those described in fibrosis of shown to act directly on osteoblastic cells by increasing for-
the lungs and cirrhosis of the liver after attacks by viruses, mation of bone56 and reducing proliferation of fibroblasts.57
alcohol, and silica.50 All patients had improved at 6 months. Sixteen of the 18
The mandible is thought to be predisposed to the devel- recovered completely, 14 within 8 months. The remaining
opment of ORN. This is principally the result of fibrosis two patients responded but not as well. This was not a
that causes the obliteration of the inferior alveolar artery controlled prospectively randomised trial, but its results are
together with the failure of the facial artery to jointly form nevertheless dramatic.
a supply. The imbalance between synthesis and degrada-
tion in irradiated tissue is particularly dramatic in bone. The
combination of death of osteoblasts after irradiation, failure New protocols for prevention and treatment of
of osteoblasts to repopulate, and excessive proliferation of osteoradionecrosis
myofibroblasts, results in a reduction in bony matrix and its
replacement with fibrous tissues. Microradiographic anal- Based on current understanding of the pathophysiology of
ysis of bone in ORN suggests four possible mechanisms ORN, new protocols could be developed for its prevention
of bony destruction: progressive resorption of osteoclasts and treatment. Previously, patients who required multiple
mediated by macrophages that are unaccompanied by osteo- dental extractions or extensive surgical extractions, or both,
genesis; periosteocytic lysis, pathognomic of ORN; extensive might have been given HBO before and after operation.
demineralisation that is secondary to external stimuli such Instead, all patients having dental extractions could be given
as saliva and bacterial products; and accelerated aging of eight weeks of pentoxifylline 400 mg twice daily with toco-
bone.51 pherol 1000 IU, starting a week before the procedure. If
Ultimately, the myofibroblasts undergo apoptosis and, ORN developed then they could be continued for a further 6
even decades after radiotherapy, the bone remains paucicel- months with clodronate prescribed after 3 months if there has
lular, poorly vascularised, and fibrosed.50 These irradiated been no appreciable response. The use of antibiotic prophy-
areas that have healed remain fragile, and may be subjected laxis before extractions, though commonplace, has not been
to surges of late reactivated inflammation after any physic- validated in any study to our knowledge. However, antimi-
ochemical trauma so that they have a tendency to develop crobial propylaxis could be incorporated into this protocol if
ORN (Fig. 2). desired.
658 A. Lyons, N. Ghazali / British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660

Fig. 2. Radiation-induced Fibroatrophic Theory.

Fig. 3. Protocol for patients who require dental extractions after radiotherapy.
 A. Lyons, N. Ghazali / British Journal of Oral and Maxillofacial Surgery 46 (2008) 653–660 659

Patients with established ORN follow this regimen for 6 report of a thirty year retrospective review. Int J Oral Maxillofac Surg
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tomy should be given pentoxifylline and tocopherol. These and neck tumors. Med Oncol 2006;23:325–34.
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